Inflammatory diseases affect the majority of population world over. Inflammatory disease include (not limiting to) tumors, arthritis, ischemic retinopathies, age-dependent macular degeneration, chronic transplant rejection, Psoriasis, Atherosclerosis, Restenosis, Obesity, pulmonary hypertension, chronic respiratory diseases, cerebral ischemia, dementia, vascular malformations, inflammatory bowel disease, osteoporosis/bone resorption, ulcerative colitis, respiratory distress syndrome, diabetes, skin delayed type hypersensitivity disorders, Alzheimer's disease, multiple sclerosis.
Psoriasis is a noncontagious chronic inflammatory dermal disease affecting about 2% of the world population [M. P. Schon and W. H. Boehncke, New England Journal of Medicine, vol. 352, no. 18, pp. 1899-1912, 2005]. Psoriasis is a skin disease that affects a person's daily life on many levels including professional and social life. The physical and psychological impacts of psoriasis are comparable to those of cancer, heart disease, diabetes, or depression [Y. Liu, et al., Genes and Immunity, vol. 8, no. 1, pp. 1-12, 2007]. Psoriasis is characterized by recurrent red and scaly skin plaques that can be easily demarcated from adjacent normal skin [K. E. Nograles and J. G. Krueger, Experimental Cell Research, vol. 317, no. 9, pp. 1293-1300, 2011]. The percentage of the body affected by psoriatic plaques can vary. It is possible to observe mild (<2%), moderate (2-10%), and severe (>10%) psoriasis in different people [S. R. Rapp, et al., Journal of the American Academy of Dermatology, vol. 41, no. 3, pp. 401-407, 1999].
The cause of the disease is unknown, though it is believed to have a genetic component, and it has been suggested to be a T-cell mediated autoimmune skin disorder. There have been many attempts to treat the disease, and several topical and systemic treatments for psoriasis which inhibit cell division have been tried, with limited success in clearing the skin for short periods of time.
The histological characteristics of many dermal inflammatory diseases include: epidermal hyperplasia (abnormal differentiation and incomplete maturation of keratinocytes), a thickened epidermis, and a reduced or absent granular layer. Psoriasis is one such disease which has been long thought to be caused by hyperproliferation of keratinocytes. However, when immunomodulatory treatments became effective, the immune system was found to be an important factor in the development of the disease. Raychaudhuri, et al. proposed in 1986 a possible role for neuropeptides in the pathogenesis of psoriasis (Raychaudhuri, P., Farber, E. M. in Psoriasis 3rd ed. (pp. 383-391).
Psoriasis is an inflammatory disease in which dendritic cells, T lymphocytes, macrophages, neutrophils, and keratinocytes are responsible for the initiation of skin lesions. Presentation of antigen and the formation of the immunological synapse causes the secretion of various cytokines/chemokines and allows the differentiation of T cells into effector cells such as Th1, Th2, and Th17. Thus, each effector cell will secrete particular cytokines.
It has been shown that IFN-α, TNF-α, and IL-2 increase the proliferation of keratinocytes [C. E. Griffiths and J. N. Barker, The Lancet, vol. 370, no. 9583, pp. 263-271, 2007]. TNF-α activates the development of lesions by increasing the number of molecules involved in the inflammatory response or the adhesion molecules. Studies on inflammatory skin models suggest that IL-23 (a key cytokine that has been found to play a critical role in the pathogenesis of psoriasis) and Th17 T cells (which produce IL-17 and IL-22) may be pivotal inducers of epidermal hyperplasia and thus may modify epidermal differentiation in inflammatory diseases [Y. Zheng et al., Nature, vol. 445, no. 7128, pp. 648-651, 2007].
In addition to genetic predisposition, several in vivo studies have shown the involvement of T helper (Th) 17 cells as well as secretion of cytokines such as interleukins and TNFα, by skin associated cells such as keratinocytes, dendritic and T helper cells, as key players in the development of the inflammatory response involved in the pathogenesis of psoriasis and other autoimmune inflammatory diseases. The secretion of cytokines such TNFα and Interleukin (IL)-23, which stimulates survival and proliferation of Th17 cells, also serves as a key master cytokine regulator for these diseases. (Fitch et al. (2007) Curr Rheumatol Rep. 9:461-7). Th17 cells within dermis in turn, induce secretion of IL-17A and IL-22. IL-22, in particular, derive keratinocyte hyperproliferation and augment the inflammatory response (Fitch et al. (2007) Curr Rheumatol Rep 9:461-7).
US20140220030 describes a method for the treatment and prevention of psoriasis by modulating the concentration of neuropeptide calcitonin gene-related peptide (CGRP) in the body, especially in the skin, e.g., by the use of CGRP antagonists. This invention is based on the notion that by changing the level of CGRP, at least in the psoriatic lesions, such as by blocking the activity of CGRP, the disease can be treated and/or prevented. This is effected by the administration of CGRP antagonist compounds, or by administering tryptase or other compounds affecting the level of CGRP. The results of this invention indicate that increased concentration in CGRP level in the skin is a very early event in the development of psoriasis. This supports that failure in regulating the GCRP level (i.e. an enhanced CGRP level) could be a causative factor in the psoriasis disease.
Although many studies have been performed on the possible causes of inflammatory diseases, the origin of the diseases such as psoriasis remains unknown. Currently, several treatments are available to help control psoriasis; however, the available treatments are only able to relieve the symptoms and lives of individuals [U. Mrowietz, et al., Archives of Dermatological Research, vol. 303, no. 1, pp. 1-10, 2011]. The choice of the most appropriate treatment depends on the patient's general health, age, comorbidities, form and severity of the pathology, and, also, on the affected body parts.
Although the treatments available for many inflammatory diseases have increased rapidly in recent years; however, they are still incomplete. For instance, although there are many drugs for different types of psoriasis, no drug can cure the disease. In addition, many of the drugs have serious side effects. Research has led to the development of new biological drugs that are produced through biotechnology which are effective for long-term. These biological treatments are an alternative to conventional treatments for moderate and severe psoriasis.
In recent years, findings on the immunologic factors related to the inflammatory diseases have changed the treatment of many of these diseases and created new biological drugs. These new classes of treatments consist in the fusion of proteins and monoclonal antibodies that specifically target the activity of T cells or inflammatory cytokines by inhibiting or modulating specific immune system factors. Biological drugs save other organs and minimize side effects.
For instance, US20140170138 relates to humanized anti-HSP65 derived peptide, specifically, peptide-6 antibodies and any antigen-binding fragments thereof. The invention relates to humanized anti-peptide-6 antibodies, compositions, methods and uses thereof for the treatment of immune-related disorders. The invention relates to a humanized antibody or any antigen-binding fragment thereof that specifically binds a polypeptide. The polypeptide known as peptide-6, is derived from HSP65.
US20130310309 provides a topical pharmaceutical composition for treating a skin disorder selected from the group consisting of Herpes viral infection, Varicella viral infection, rash, insect bites, jellyfish stings, burns, psoriasis, itching, skin allergic response, skin lesions as a result of drug or medical treatment side effects or complications, and hypopigmentation. The composition comprises a peptide of the formula pGLU-X-Y-Z, where X, Y and Z are amino acids, with or without an alkyl group, and a pharmaceutically acceptable excipient.
US20130296250 provides a method and kit for treatment of psoriasis using protein kinase C (PKC)-alpha inhibitors. Exemplary inhibitors include peptide PKC-alpha inhibitors which specifically inhibit PKC-alpha activity leading to the attenuation and treatment of psoriasis.
US20130210707 provides a peptide having antibacterial or anti-inflammatory activity and a pharmaceutical composition containing the same as an active ingredient, and more particularly to a peptide having antibacterial or anti-inflammatory activity against dental bacteria, including periodontal pathogens, and bacteria causing atopic dermatitis, and to a pharmaceutical composition containing the peptide as an active ingredient. The peptide having antibacterial or anti-inflammatory activity can be used for the treatment of both dental infectious diseases, including periodontitis or peri-implantitis, and inflammations, including atopy, psoriasis or arthritis.
However, these treatments have a high cost and significant side effects. Research continues to elucidate new pathological mechanisms and develop new proteins for treatment of inflammatory diseases such as psoriasis. These proteins participate in biological processes involved in the immune response to psoriasis and are found in all cells.
In addition, while psoriasis is considered a topical chronic skin disease, many of the existing effective drugs are systemic, which are based on immune suppression and as a result appear to lead to adverse effects, of which some can be severe. On the other hand, current topical treatments to psoriasis appear to be only moderately effective in reducing symptoms and overcoming pathology. This situation leads to the apparent practice that psoriasis patients commonly visit multiple doctors in a short period of time, indicating their dissatisfaction with available care. As a result, there is a strong need for an effective therapeutic alternative which targets multiple components of the disease's pathogenesis, while retaining a low level of side effects.
Accordingly the present invention provides a cost effective, non-toxic peptide having anti-inflammatory activity, and which is effective for the treatment of inflammatory disease such as.